Targeting Src Kinases in Head and Neck Cancer Head and neck squamous cell carcinoma (HNSCC) are common worldwide and are particularly difficult to treat because both the tumor and the treatment can impair essential functions, such as speech and swallowing, and severely alter facial appearance. Local invasion is a critical determinant of both morbidity and mortality for HNSCC and is associated with worse locoregional control and decreased survival. There is a critical need to improve systemic therapy to treat both local invasion and distant metastatic disease. One promising molecular target in HNSCC for which new agents have been developed is c-Src. Inhibition of c-Src causes a significant and universal inhibition of migration and invasion of HNSCC cells; however, the cytotoxic effects of c-Src inhibition are less predictable. Defining mechanisms that limit the cytotoxic effects of c-Src inhibitors may result in an ideal combination of therapeutic agents for HNSCC that inhibits both local invasion and leads to significant cytotoxicity. As STATs can mediate proliferation and survival downstream of c-Src, we studied the role of STATs in modulating the effects of c-Src inhibition. We discovered a novel feedback pathway that leads to the reactivation of STAT3 via JAK which mediates resistance to c-Src inhibitors. We investigated feedback pathways leading to STAT3 activation and found that c-Src inhibition leads to down- regulation of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of JAK/STAT3. Blockade of this feedback pathway significantly enhances the cytotoxic effect of c-Src inhibition. We hypothesize that sustained c-Src kinase inhibition leads to JAK/STAT3 reactivation via a novel feedback pathway involving SOCS2 and that inhibition of this feedback pathway will enhance the therapeutic efficacy of c-Src inhibition. We will test this hypothesis with three specific aims: To elucidate the mechanism underlying the feedback loop leading to STAT3 activation following sustained c-Src inhibition in HNSCC; to evaluate whether JAK inhibition enhances the therapeutic efficacy of the c-Src inhibitor dasatinib in an orthotopic model of HNSCC; and to develop and characterize a heterotransplant model of HNSCC in which to test biologic and signaling effects of c-Src and JAK inhibition. In the latter aim, we will evaluate the feedback pathway in a novel patient-derived heterotransplant model that could serve as a better surrogate for therapeutic studies in human HNSCC. Our long-term goal is to translate these findings into a future clinical trial in HNSCC patients that will test the efficacy of dual-targeting JAK and c-Src inhibition to improve treatment options for this deadly disease.